Article Dans Une Revue Nature Genetics Année : 2023

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Changuk Chung (1, 2) , Xiaoxu Yang (1, 2) , Taejeong Bae (3) , Keng Ioi Vong (1, 2) , Swapnil Mittal (1, 2) , Catharina Donkels (4) , H. Westley Phillips (5) , Zhen Li (1, 2) , Ashley P L Marsh (1, 2) , Martin W Breuss (1, 2) , Laurel L Ball (1, 2) , Camila Araújo Bernardino Garcia (6) , Renee D George (1, 2) , Jing Gu (1, 2) , Mingchu Xu (1, 2) , Chelsea Barrows (1, 2) , Kiely N James (1, 2) , Valentina Stanley (1, 2) , Anna S Nidhiry (1, 2) , Sami Khoury (1, 2) , Gabrielle Howe (1, 2) , Emily Riley (1, 2) , Xin Xu (1, 2) , Brett Copeland (1, 2) , Yifan Wang (3) , Se Hoon Kim (7) , Hoon-Chul Kang (7) , Andreas Schulze-Bonhage (4) , Carola A Haas (4) , Horst Urbach (8) , Marco Prinz (8, 4) , David D Limbrick (9, 10) , Christina A Gurnett (9, 10) , Matthew D Smyth (9, 10) , Shifteh Sattar (11) , Mark Nespeca (11) , David D Gonda (11) , Katsumi Imai (12) , Yukitoshi Takahashi (12) , Hsin-Hung Chen (13) , Jin-Wu Tsai (14) , Valerio Conti (15, 16) , Renzo Guerrini (15, 16) , Orrin Devinsky (17) , Wilson A Silva (6) , Helio R Machado (6) , Gary W Mathern (5) , Alexej Abyzov (3) , Sara Baldassari (18, 19) , Stéphanie Baulac (18, 19) , Joseph G Gleeson (1, 2)
1 UC San Diego - University of California [San Diego]
2 Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
3 Mayo Clinic [Rochester]
4 Albert-Ludwigs-Universität Freiburg = University of Freiburg
5 UCLA - University of California [Los Angeles]
6 USP - Universidade de São Paulo = University of São Paulo
7 Yonsei University
8 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
9 St. Louis Children's Hospital
10 WUSTL - Washington University in Saint Louis
11 Rady Children's Hospital
12 University of Shizuoka = Université préfectorale de Shizuoka
13 Taipei Veterans General Hospital [Taiwan]
14 NYCU - National Yang Ming Chiao Tung University [Taipei]
15 AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
16 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
17 NYU Langone Medical Center - New York University Langone Medical Center
18 ICM - Institut du Cerveau = Paris Brain Institute
19 CHU Pitié-Salpêtrière [AP-HP]
Changuk Chung
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Xiaoxu Yang
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Taejeong Bae
  • Fonction : Auteur
Mayo Clinic [Rochester]
Keng Ioi Vong
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Swapnil Mittal
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Catharina Donkels
Albert-Ludwigs-Universität Freiburg = University of Freiburg
H. Westley Phillips
UCLA - University of California [Los Angeles]
Zhen Li
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Ashley P L Marsh
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Martin W Breuss
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Laurel L Ball
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Camila Araújo Bernardino Garcia
  • Fonction : Auteur
USP - Universidade de São Paulo = University of São Paulo
Renee D George
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Jing Gu
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Mingchu Xu
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Chelsea Barrows
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Kiely N James
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Valentina Stanley
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Anna S Nidhiry
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Sami Khoury
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Gabrielle Howe
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Emily Riley
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Xin Xu
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Brett Copeland
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
Yifan Wang
Mayo Clinic [Rochester]
Se Hoon Kim
Yonsei University
Hoon-Chul Kang
  • Fonction : Auteur
Yonsei University
Andreas Schulze-Bonhage
  • Fonction : Auteur
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Carola A Haas
  • Fonction : Auteur
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Horst Urbach
  • Fonction : Auteur
Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
Marco Prinz
Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
Albert-Ludwigs-Universität Freiburg = University of Freiburg
David D Limbrick
  • Fonction : Auteur
St. Louis Children's Hospital
WUSTL - Washington University in Saint Louis
Christina A Gurnett
  • Fonction : Auteur
St. Louis Children's Hospital
WUSTL - Washington University in Saint Louis
Matthew D Smyth
  • Fonction : Auteur
St. Louis Children's Hospital
WUSTL - Washington University in Saint Louis
Shifteh Sattar
  • Fonction : Auteur
Rady Children's Hospital
Mark Nespeca
  • Fonction : Auteur
Rady Children's Hospital
David D Gonda
  • Fonction : Auteur
Rady Children's Hospital
Katsumi Imai
  • Fonction : Auteur
University of Shizuoka = Université préfectorale de Shizuoka
Yukitoshi Takahashi
  • Fonction : Auteur
University of Shizuoka = Université préfectorale de Shizuoka
Hsin-Hung Chen
Taipei Veterans General Hospital [Taiwan]
Jin-Wu Tsai
  • Fonction : Auteur
NYCU - National Yang Ming Chiao Tung University [Taipei]
Valerio Conti
  • Fonction : Auteur
AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
Renzo Guerrini
  • Fonction : Auteur
AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
Orrin Devinsky
  • Fonction : Auteur
NYU Langone Medical Center - New York University Langone Medical Center
Wilson A Silva
USP - Universidade de São Paulo = University of São Paulo
Helio R Machado
  • Fonction : Auteur
USP - Universidade de São Paulo = University of São Paulo
Gary W Mathern
  • Fonction : Auteur
UCLA - University of California [Los Angeles]
Alexej Abyzov
Mayo Clinic [Rochester]
Sara Baldassari
  • Fonction : Auteur
ICM - Institut du Cerveau = Paris Brain Institute
CHU Pitié-Salpêtrière [AP-HP]
Stéphanie Baulac
  • Fonction : Auteur
ICM - Institut du Cerveau = Paris Brain Institute
CHU Pitié-Salpêtrière [AP-HP]
Joseph G Gleeson
  • Fonction : Auteur
UC San Diego - University of California [San Diego]
Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]

Résumé

Malformations of cortical development (MCD) are neurological conditions displaying focal disruption of cortical architecture and cellular organization arising during embryogenesis, largely from somatic mosaic mutations, and causing intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here, we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associating distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains implicate critical roles in excitatory neurogenic pools during brain development, and in promoting neuronal hyperexcitability after birth.

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Soumis le : jeudi 13 juin 2024-10:45:23

Dernière modification le : mercredi 2 juillet 2025-11:34:02

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hal-04610563 , version 1 (13-06-2024)

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CC BY-NC-ND 4.0 - Attribution - Utilisation non commerciale - Pas d’oeuvre dérivée

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Changuk Chung, Xiaoxu Yang, Taejeong Bae, Keng Ioi Vong, Swapnil Mittal, et al.. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development. Nature Genetics, 2023, 55 (2), pp.209-220. ⟨10.1038/s41588-022-01276-9⟩. ⟨hal-04610563⟩

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